Flushing Disorders Associated with Gastrointestinal Symptoms: Part 2, Systemic Miscellaneous Conditions

Vaibhav Rastogi, MD; Devina Singh, MD; Joseph J. Mazza, MD; Dipendra Parajuli, MD, and Steven H. Yale, MD

Flushing disorders with involvement of the gastrointestinal tract represent a heterogeneous group of conditions. In part 1 of this review series, neuroendocrine tumors (NET), mast cell activation disorders (MCAD), and hyperbasophilia were discussed. In this section we discuss the remaining flushing disorders which primarily or secondarily involve the gastrointestinal tract. This includes dumping syndrome, mesenteric traction syndrome, rosacea, hyperthyroidism and thyroid storm, anaphylaxis, panic disorders, paroxysmal extreme pain disorder, and food, alcohol and medications. With the exception of paroxysmal pain disorders, panic disorders and some medications, these disorders presents with dry flushing. A detailed and comprehensive family, social, medical and surgical history, as well as recognizing the presence of other systemic symptoms are important in distinguishing the different disease that cause flushing with gastrointestinal symptoms.

Keywords: Flushing; Gastrointestinal; Human; Panic disorder; Dumping syndrome

euroendocrine tumors, mast cell disorders, and differentiated based on a comprehensive history that should hyperbasophilia are diseases that arise from the include duration, frequency, and factors that triggers gastrointestinal tract or causes gastrointestinal symptoms since in some of these diseases there are no N biomarkers to confirm the disease. symptoms and were covered in part 1 of this review. These diseases vary based on their malignant potential, and all cause dry flushing, with diagnosis based on biochemical Methods properties and in some cases histopathology obtained from A description of the methodological approach to this review tissue and/or bone marrow biopsy. can be found in Part 1, Neuroendocrine Tumors, Mast Cell Disorders, and Hyperbasophilia. In Part 2 of this review, we cover common and rare causes of flushing, including dumping syndrome, mesenteric traction Dumping Syndrome syndrome, rosacea, hyperthyroidism and thyroid storm, Dumping syndrome is a condition characterized by rapid anaphylaxis, panic disorders, paroxysmal extreme pain emptying of the contents of the stomach into the small disorder, and food, alcohol and medications. These are a intestines postprandially. It occurs post-operatively after heterogeneous group of disease that share similar non- esophageal, bariatric, and gastric surgery, and in patients with specific gastrointestinal symptoms including nausea, diarrhea diabetes mellitus. In some patients the condition is idiopathic.1 and abdominal pain (Figure 1). These conditions are This syndrome occurs in approximately 20% of patients

Corresponding Author: Steven H. Yale MD, University of Central Florida College Received: July 31, 2017 of Medicine, HCA Consortium Graduate Medical Education, North Florida Regional Revised: November 30, 2017 Medical Center, 6500 W Newberry Rd, Gainesville, FL 32605, Tel: (715) 383-0928, Accepted: December 21, 2017 Email: [email protected] doi: 10.3121/cmr.2017.1379b

29 Figure 1. Diagnostic approach to flushing with and without gastrointestinal symptoms. undergoing pylorotomy and vagotomy, 40% post-roux-en-y suggests it occurs after eventeration and manipulation, and it gastric bypass or sleeve gastrectomy, and 50% after was initially called eventeration syndrome.5 esophagectomy procedures.2 Pathogenesis is due to alterations in gastric anatomy or its innervation mediated by various Clinical Presentation and Gastrointestinal Involvement gastrointestinal peptides such as vasoactive intestinal The triad of flushing, hypotension, and tachycardia polypeptide, neurotensin, and incretins.2,3 characterizes MTS. Episodes last for approximately 30 minutes.5 Mast cells and endothelial cells are primarily Clinical Presentation and Gastrointestinal Involvement involved in the pathogenesis with prostacyclin (PGI2) release Early and late variants of dumping syndrome have been suggested to be the primary mediator of this syndrome.5 Other described depending upon the timing of symptom onset mediators involved include histamine, bradykinin, nitric oxide (within 1 hour or up to 3 hours) postprandially.2 Symptoms and serotonin. caused by the rapid hyperosmolar load transmitted from the stomach to the small intestines consist of abdominal cramps, Diagnosis and Treatment diarrhea, nausea, vomiting, and postprandial fatigue. Flushing, Mesenteric traction syndrome is a clinical diagnosis. palpitations, perspiration, hypotension, tachycardia and Cyclooxygenase inhibitors are used to treat or prevent the headache also occur with elevated bradykinin levels occurrence of this syndrome.4 Other classes of medications implicated in causing flushing.1 used include histamine-1 antagonists and serotonin receptor antagonists.5 Diagnosis and Treatment Glucose challenge test and gastric emptying scintigraphy are Rosacea diagnostic. Non-pharmacologic treatments include consuming Rosacea is a chronic relapsing inflammatory and vascular skin smaller and more frequent meals supplemented with fiber and disorder of unknown etiology. Prevalence ranges from 1% to protein1 and medications such as acarbose, octreotide, 20% and typically occurs in patients after the third decade of diazoxide, loperamide, and nifedipine.2 Surgical approaches life.6 It most commonly involves the central face and occurs or continuous enteral feeding should be considered in principally in fair-skinned individuals.7 Genetic and refractory disease.2 environmental factors are believed to account for the pathogenesis of this disease. Risk factor for development of Mesenteric Traction Syndrome the disease includes family history, lighter phototypes, Mesenteric traction syndrome (MTS) is a rare condition seen increased alcohol consumption, and excessive ultraviolet in the early phase of abdominal upper gastrointestinal, exposure.6 Of the four subtypes of rosacea established by the pancreatic, and abdominal vascular surgery.4 As the name National Rosacea Society, flushing occurs in subtype 1 or

30 Flushing associated with gastrointestinal system CM&R 2018 : 1-2 (June) erythmatotelangiectatic variant.6,8,9 Prolonged flushing and hormone include diarrhea, malabsorption, nausea, vomiting erythema with or without telangiectasias involves the face, and abdominal pain caused by increased gut motility. Goiter ears, neck and upper trunk. Patients may also report edema, can cause local esophageal compression and dysphagia.18 rough or scaly skin, edema and stinging or burning sensation Cutaneous symptoms include warmth, flushing, sweating, suggestive of an antidromic autonomic response to pruritus, and thinning of the hair. Other constitutional and vasodilation.9,10 clinical manifestations include weight loss, tremors, palpitations, dyspnea, fatigue, sleep abnormalities and Flushing and increased blood flow is believed to be the result diplopia.18 of vasodilatory neural stimuli and humoral release of a variety of mediators that includes the neuropeptides vascular Additional symptoms that may occur in thyroid storm include endothelial growth factor (VEGF), vasoactive intestinal tachycardia, agitation, hyperthermia, psychosis, severe peptide (VIP), substance P, and acetylcholine (Ach).9,11 dyspnea, diarrhea, nausea, vomiting, flushing, and hepatitis.19,20 Evidence for a neurogenic component is further suggested by the findings of upregulation of neuropeptide genes: VIP, Diagnosis and Treatment pituitary adenylate cyclase-activating polypeptide (PACP), Tests of thyroid function (thyroid stimulating hormone, free 5-hydyroxytryptmine 3A receptors, nerve growth factor beta, and total T4, free and total T3) are used to confirm the alpha-1D adrenergic receptors, adrenomedullin 2, and diagnoses. Treatment for hyperthyroidism involves anti- cathelicidin antimicrobial peptide.11,12 Transient receptor thyroid medication, surgery, and radioactive iodine therapy.18 potential vanilloid of cation channels and ankyrin receptors Thyroid storm requires treatment with beta-blockers for may also contribute to flushing and burning.13 symptomatic management and iodine and thioamide (methimazole) to prevent synthesis and release of thyroid Clinical Presentation and Gastrointestinal Involvement hormone. Corticosteroids and iodinated radiocontrast agent Flushing and facial redness is a sign of early disease. block peripheral T4 to T3 conversion and have also been Symptoms are recurrent lasting up to 3 hours.6 Some studies found useful in management.19,20 suggest an association between rosacea and gastrointestinal tract disorders including celiac disease, irritable bowel Anaphylaxis syndrome, inflammatory bowel disease, small intestinal Anaphylaxis is an acute potentially lethal condition involving overgrowth and Helicobacter pylori infection.7,14,15 The multiple organ systems caused by the abrupt release of pathogenesis behind this relationship remains unknown. mediators from mast cell and/or basophils.21,22 Immunoglobulin G (IgG), IgE and complements play an important role in the Diagnosis and Treatment pathophysiology of anaphylactic patients.22 Most cases are Rosacea is diagnosed clinically based on characteristic related to food, drugs (penicillins) and insect stings while one- features.7 Measures to prevent flushing involve avoiding third are idiopathic. Some patients may have a genetic triggers such as protection from ultraviolet rays from the sun, predisposition such as in hereditary angioedema.22 The spicy food, hot beverages and alcohol.8 Pharmacologic incidence of anaphylaxis in the United State is approximately management includes metronidazole, azelaic acid, ivermectin, 1% to 3%.22 Anaphylactoid reactions, which clinically resemble or sulfur preparations.16 Erythema of the face can be managed anaphylaxis, are often precipitated by non-IgE related with topical α adrenergic receptor agonists such as brimonidine mechanisms. tartrate gel 0.05%.17 Progressive and severe disease is treated with oral antibiotics and retinoids, and laser procedures are Clinical Presentation and Gastrointestinal Involvement used to treat telangiectasia and rhinophyma.16 Cutaneous symptoms of flushing, angioedema, and urticaria are found in the majority of patients.23 Gastrointestinal Hyperthyroidism and Thyroid Storm manifestations including abdominal pain, nausea, vomiting Hyperthyroidism, a condition caused by elevated thyroid and diarrhea.22 Severe symptoms may include shortness of hormone production, has a prevalence of 1.3% in United breath, laryngospasm, coughing, congestion, choking, States.18 It is more common in females with the incidence tachycardia, hypotension, syncope, and dizziness. increasing by age. Conditions that cause hyperthyroidism, including Grave’s disease, Hashitoxicosis, toxic adenoma, Diagnosis and Treatment multi-nodular goiter and thyroiditis, may cause flushing.18 Diagnosis is primarily clinically based with the treatment of Thyroid storm is a condition resulting in the acute increase in choice being emergent administration of intramuscular or thyroid hormone levels. It can be precipitated by aberrant intravenous epinephrine.21 Confirmatory markers, although discontinuation or improper dosing of anti-thyroid not generally obtained, include finding an elevated tryptase medications, thyroid or non-thyroidal surgery, infection, level indicative of mast cell degranulation. In non-emergent trauma and parturition. cases, allergy or prick testing can be pursued to identify the culprit allergen.21 Clinical Presentation and Gastrointestinal Involvement Gastrointestinal manifestations related to excess of thyroid

CM&R 2018 : 1-2 (June) Rastogi et al. 31 Panic Disorder with panic disorder may be responsible for symptoms of The American Psychiatric Association classifies panic irritable bowel syndrome due to interactions between the disorder as an anxiety disorder in DSM-5 that is a clinical central and enteric nervous system.30 syndrome characterized by recurrent autonomic and dissociative clinical symptoms and intense irrational fear and Diagnosis and treatment discomfort of recurrence. Symptoms occur spontaneously or Diagnosis is based on identifying at least four physical and in response to a known trigger, peak within minutes and last psychological symptoms. Medical and psychotherapy alone or for few minutes to an hour.24,25 Currently, lifetime presence in combination, particularly in patients with moderate to of panic disorder in the United States in patients between the severe disease, are effective in preventing and controlling ages of 15 years and 54 years is approximately 4% to 7%. It symptoms. Medications used to treat panic disorders include is believed that around 33% of people may have at least one anti-depressants, benzodiazepines, and selective serotonin panic attack at some time during their lives.26 reuptake inhibitors, with the latter considered as first line therapy.24 Clinical Presentation and Gastrointestinal Involvement Diagnoses requires the presence of a minimum of four of 13 Parosysmal Extreme Pain Disorder symptoms including palpitations, chest pain, sweating, Paroxysmal Extreme Pain Disorder (PEPD), formerly named shaking, dizziness, flushing, stomach churning, numbness, Familial Rectal Pain Syndrome, is a rare autosomal dominant choking feeling, hot or cold sensation, de-realization, clinical syndrome characterized in adults primarily by breathlessness and fear of losing control or dying, along with excruciating burning pain in the rectal, ocular and mandibular concerns about maladaptive behavioral changes resulting in regions and lower body, autonomic (flushing, rhinorrhea, an attempt to avoid further episodes (Table 1).24,25 Flushing diaphoresis), cardiovascular (bradycardia, asystole, syncope), in panic disorder is of the wet type associated with activation and tonic nonepileptic seizures. Symptoms occur in response of the autonomic nervous system and stimulation of eccrine to benign mechanical triggers such as defecation (rectal crisis), sweat glands.27 yawning and eating (mandibular crisis), spontaneously (ocular crisis) as well as cold temperatures and emotional factors.33-36 Panic disorder may be linked to structural and functional gastrointestinal diseases including peptic ulcer disease, PEPD is caused by a heterozygous missense mutation (gain of gastritis, irritable bowel syndrome and chest pain of function) in the SCN9A gene expressed in peripheral sensory esophageal origin.28-31 Studies suggest that cholecystokinin nerves of the dorsal root and sympathetic ganglion neurons might be a common mediator between functional that encode the alpha-subunit of Nav1.7 voltage-gated sodium gastrointestinal diseases and panic disorder.32 Dysregulation channel. This sodium channel is responsible for the generation within the locus coeruleus of the brainstem area in patients and propagation of the action potential in primary afferent

Table 1. Four DSM-5 Criteria for Panic Disorder Based Flushing25 A. Four or more of the following symptoms occurring during a panic attack 1. Palpitations, pounding heart or accelerated heart rate. 2. Sweating 3. Trembling or shaking 4. Sensation of shortness of breath or smothering 5. Feeling of choking 6. Chest pain or discomfort 7. Nausea or abdominal distress 8. Feeling dizzy, unsteady, light-headed, or faint 9. Chills or heat sensations. 10. Paresthesias 11. Derealization or depersonalization 12. Fear of losing control 13. Fear of dying B. At least one of the attacks has been followed by at least one month of one or both of the following: 1. Persistent concern or worry about additional panic attacks or their consequences 2. A significant maladaptive change in behavior related to the attack(s). C. The disturbance is not attributable to the physiological effects of a substance or another medical condition. D. The disturbance is not better explained by another mental disorder

32 Flushing associated with gastrointestinal system CM&R 2018 : 1-2 (June) sensory and sympathetic autonomic nerve fibers.35 Alterations impaired metabolism and accumulation of acetaldehyde.21,44 in closure of the channel leads to enhanced cellular Abstinence from alcohol in those who lack aldehyde depolarization allowing more channels to remain open and dehydrogenase or who are consuming medications that inhibit hyperexcitable at the defined membrane potential.35,37 aldehyde dehydrogenase prevents symptoms.21

Clinical Presentation and Gastrointestinal Involvement Improper or delayed refrigeration of primarily dark meat fish PEPD is an autosomal dominant disease. Symptoms begin (mainly tuna from Scrombridae and Scromberescidae families) during the neonatal period and progress with increasing age.38 may cause symptoms consisting of flushing, sweating, Patients and affected family members present with visceral headache, cramping abdominal pain, nausea, vomiting and pain paroxysms and diverse symptoms based on the severity, diarrhea to occur shortly after consumption.45-47 Other fish of locations and duration of symptoms.34,35 Patient may initially the non-scromboid family (eg, swordfish, spotted sardines) complain of pruritus followed by burning pain that when have also been reported to cause this syndrome. Histamine is severe is described as sharp, stabbing or lancinating, lasting the main mediator for the symptoms of scombroid fish for seconds to hours and gradually subsides with time.34 poisoning and is caused by bacteria within the fish, which Although pain may initially start in a specific region, during under warm conditions converts histidine to histamine by the severe attacks it may become more widespread and affect the enzyme histamine decarboxylase. Cooking kills the bacteria entire body.34 Flushing and diaphoresis are mediated through but histamine remains intact since it is heat stable. Symptoms dysfunction of autonomic nerves and typically occur at the generally resolve within 24 hours. Antihistaminic medications pain site. Constipation is commonly reported between are used in symptom management.45,46 attacks.34 In contrast to ocular and mandibular crises, the frequency and severity of rectal crisis tends to decrease with Ingestion of the inocybe mushroom has been reported to cause advancing age.34 an acute syndrome of flushing, nausea, vomiting, diarrhea, abdominal pain and a variety of muscarinic manifestations Diagnosis and Treatment including hypersalivation, diaphoresis, bradycardia, PEPD is a clinical diagnosis based on signs and symptoms lacrimation, and blurred vision.48 Treatment is supportive and that vary among affected individuals and family members. includes intravenous fluids, atropine and antiemetics.48 Genetic sequencing of SCN9A may assist in confirming the diagnosis. Medical therapy including amitriptyline, Sulphides used as a preservative and additive to food and gabapentin, carbamazepine, topiramate, valproic acid and drinks has also been reported to cause symptoms of flushing, tiagabine has shown variable effectiveness in reducing the abdominal pain, diarrhea, urticaria and hypotension in frequency and severity of attacks.38 Non-pharmacologic susceptible individuals.49 Preventive measures include measures involve pelvic floor retraining with biofeedback.39 avoiding food and beverage containing high concentration of sulphides such as grape, lemon or lime juice, wine and most Table 1. Four DSM-5 Criteria for Panic Disorder Based Flushing25 Food, Alcohol and Medications dry fruits. Flushing and alterations in gastrointestinal motility occur A. Four or more of the following symptoms occurring during a panic attack with a variety of medications and chemotherapeutic agents Conclusion 1. Palpitations, pounding heart or accelerated heart rate. including cholinergic agents, morphine, catecholamines, The differential diagnosis of flushing can be challenging, since 2. Sweating vancomycin, rifampicin, doxorubicin, selective serotonin it encompasses both benign and malignant conditions and 40,41 3. Trembling or shaking reuptake inhibitors, tramadol and cyclosporine (Table 2). includes a wide variety of overlapping non-specific 4. Sensation of shortness of breath or smothering Gastrointestinal symptoms include diarrhea, abdominal pain, gastrointestinal symptoms. Initial evaluation involves nausea and vomiting. The mechanism precipitating symptoms obtaining a detailed history and physical examination inquiring 5. Feeling of choking and the presence of other clinical features vary depending on about the frequency and duration of the attacks, temporal 6. Chest pain or discomfort the offending agent.21,42 Treatment involves symptomatic factors, description and location, and precipitating factor(s). 7. Nausea or abdominal distress management, dose adjustment or discontinuation of the Food, beverages and alcohol are the most prevalent causes for 8. Feeling dizzy, unsteady, light-headed, or faint responsible medication. Pretreatment, in some cases, with flushing in combination with gastrointestinal symptoms anti-histaminergics can prevent the development of 9. Chills or heat sensations. (usually nausea, vomiting and diarrhea). Inquiry should be symptoms.42 made into whether the patient experiences episodes of intense 10. Paresthesias fears or discomfort associated with a variety of non-specific 11. Derealization or depersonalization Alcohol, a vasodilator, is another agent that may cause symptoms such as palpitations, trembling, sweating and chest 12. Fear of losing control flushing accompanied by nausea and vomiting particularly in pain suggestive of a panic disorder. The constellation of 13. Fear of dying susceptible individuals who lack the enzyme aldehyde flushing, diarrhea and hypotension suggests mast cell activation dehydrogenase involved in alcohol metabolism. It is believed syndromes, anaphylaxis, pheochromocytomas, scromboid B. At least one of the attacks has been followed by at least one month of one or both of the following: to be genetically determined and is most commonly found in poisoning, and carcinoid syndrome. Absence of sweating and 1. Persistent concern or worry about additional panic attacks or their consequences the Asian population.43 Additionally, inhibition of aldehyde pruritus with burning pain and flushing may be helpful in 2. A significant maladaptive change in behavior related to the attack(s). dehydrogenase by disulfiram or other disulfiram-like inducing narrowing the differential diagnosis to a mast cell activation C. The disturbance is not attributable to the physiological effects of a substance or another medical condition. agents such as chloramphenicol, furazolidone, metronidazole, disorder. Asking the patient to maintain a diary for 2 weeks D. The disturbance is not better explained by another mental disorder cephaperazone, tolbutamide can cause flushing due to recording the time of occurrence and factor that triggered the

CM&R 2018 : 1-2 (June) Rastogi et al. 33 Commonly Reported Adverse Gastrointestinal Side Effect Commonly Reported Abdominal pain or discomfort, nausea Constipation, decreased motility Nausea, vomiting Fecal Incontinence, nausea, vomiting Constipation, diarrhea, dysgeusia, flatulence, pancreatitis Constipation, diarrhea, flatulence,heartburn, stomach pain, nausea, vomiting Abdominal cramps, constipation,dyspepsia, diarrhea, vomiting Diarrhea, Hepatotoxicity Abdominal pain, diarrhea, dyspepsia, flatulence, nausea, peptic ulcer disease, vomiting Abdominal pain, diarrhea, flatulence, nausea, pseudomembranous colitis, vomiting, pancreatitis Abdominal pain, vomiting Nausea, vomiting Abdominal cramps, diarrhea, dyspepsia, colitis, ulcerations Abdominal discomfort, Abdominal cramps, diarrhea, dyspepsia, nausea, vomiting Hemorrhage, perforation, nausea, pancreatitis, vomiting, Peptic Ulcer , Abdominal cramps, constipation,diarrhea, dyspepsia, nausea Constipation, nausea, vomiting Dyspepsia, diarrhea, gastritis, nausea, vomiting Abdominal cramps, diarrhea, flatulence, nausea, vomiting Dyspepsia, gastroesophageal reflux, nausea, vomiting 21,52 21,52 21,52,53 21,54 21,52,53 21,55 21,52,53 21,54 21,52 21,52 21,52 21,52 50 21,52 21,52 52 21,52 21,52 51 Beta Blockers (Metoprolol) Angiotensin Converting Enzyme Inhibitors (Lisinopril, Ramipril) Tamoxifen, Dacarbazine, Flutamide) Tamoxifen, Amifostine Calcium Channel Blockers (Nifedipine, Diltiazem, Verapamil) Amyl Nitrate Medications that Cause Flushing and Gastrointestinal Adverse Drug Effects 2. MedicationsCause that Flushing and Gastrointestinal Table Drug Class Antiarrhythmic (Adenosine) Anticholinergics Antidote Antihypertensives Anti-emetics (Metoclopramide) Antihyperlipidemic (Nicotinic Acid) Amphotericin B) Rifampicin, Antimicrobials (Vancomycin, Antianginal (Nitroglycerine) Catecholamines (Epinephrine, norepinephrine, dopamine) Chemotherapeutics (Cyclosporine, Doxorubicin, Cisplatin, Interferon alfa-2, Cholinergics (Pilocarpine) ([oral]) Triamcinolone Corticosteroids (Methylprednisolone, Dopamine Agonists (Bromocriptine) Opioids (Morphine) Taladafil) Phosphodiesterase Inhibitors (Sildafenil, Prostaglandins (Prostaglandin E) Uricosurics (Probenicid)

34 Flushing associated with gastrointestinal system CM&R 2018 : 1-2 (June) flushing episode may be helpful in cases were the history is 17. Shanler SD, Ondo AL. Successful treatment of the erythema and not clear or incomplete during initial assessment. flushing of rosacea using a topically applied selective alpha1- adrenergic receptor agonist, oxymetazoline. Arch Dermatol 2007;143(11):1369-1371. Recognizing the pattern of disease and key clinical features 18. De Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet through the history provides important clues in initial 2016;388(10047):906-918. assessment. Obtaining specific biochemical tests is based on 19. Chiha M, Samarasinghe S, Kabaker AS. Thyroid Storm: an pre-test probability of disease. Radiologic imaging, if required, updated review. J Intensive Care Med 2015;30(3):131-140. should be obtained after the results from biochemical testing 20. Hambleton C, Buell J, Saggi B, Balart L, Shores NJ, Kandil E. Thyroid storm complicated by fulminant hepatic failure: case are available. Confirmatory diagnosis may require tissue or report and literature review. Ann Otol Rhinol Laryngol bone marrow biopsy in specific cases. 2013;122(11):679-682. 21. Izikson L, English JC III, Zirwas MJ. The flushing patient: Acknowledgement Differential diagnosis, workup, and treatment. J Am Acad The authors would like to thank Dr. Hale Toklu and Ms. Dermatol 2006;55(2):193-208. 22. Kemp SF, Lockey RF. Anaphylaxis: A review of causes and Megan Hubbard for their contributions. mechanisms. J Allergy Clin Immunol 2002;110(3):341-348. 23. Mali S, Jambure R. Anaphyllaxis management: Current References concepts. Anesth Essays Res 2012;6(2):115-123. 1. Berg P, McCallum R. Dumping Syndrome: A Review of the 24. Gnanavel S, Robert RS. Diagnostic and statistical manual of Current Concepts of Pathophysiology, Diagnosis, and mental disorders, fifth edition, and the impact of events scale- Treatment. Dig Dis Sci 2016;61(1):11-18. revised. Chest 2013;144(6):1974. 2. van Beek AP, Emous M, Laville M, Tack J. Dumping syndrome 25. Diagnostic and Statistical Manual of Mental Disorders. 5th after esophageal, gastric or bariatric surgery: pathophysiology, edition ed. Washington, DC: American Psychiatric diagnosis, and management. Obes Rev 2017;18(1):68-85. Association; 2013. 3. Sirinek KR, O’Dorisio TM, Howe B, et al. Neurotensin, 26. Kessler RC, Chiu WT, Jin R, Ruscio AM, Shear K, Walters EE. vasoactive intestinal peptide, and Roux-en-Y The epidemiology of panic attacks, panic disorder, and gastrojejunostomy. Their role in the dumping syndrome. Arch agoraphobia in the National Comorbidity Survey Replication. Surg 1985;120(5):605-609. Arch Gen Psychiatry 2006;63(4):415-424. 4. Takahashi H, Shida D, Tagawa K, Suzuki T. Hemodynamics of 27. Davies SJC, Jackson PR, Lewis G, Hood SD, Nutt DJ, Potokar mesenteric traction syndrome measured by FloTrac sensor. J JP. Is the association of hypertension and panic disorder Clin Anesth 2016;30:46-50. explained by clustering of autonomic panic symptoms in 5. Avgerinos DV, Theoharides TC. Mesenteric traction syndrome or hypertensive patients? J Affect Disord 2008;111(2-3):344-350. gut in distress. Int J Immunopathol Pharmacol 28. Goodwin RD, Cowles RA, Galea S, Jacobi F. Gastritis and 2005;18(2):195-199. mental disorders. J Psychiatr Res 2013;47(1):128-132. 6. Tan J, Berg M. Rosacea: Current state of epidemiology. J Am 29. Lydiard RB, Greenwald S, Weissman MM, Johnson J, Drossman Acad Dermatol 2013;69(6)(Suppl 1):S27-S35. DA, Ballenger JC. Panic disorder and gastrointestinal 7. Egeberg A, Weinstock LB, Thyssen EP, et al. Rosacea and symptoms: findings from the NIMH Epidemiologic gastrointestinal disorders: a population-based cohort study. Br Catchment Area project. Am J Psychiatry 1994;151(1):64-70. J Dermatol 2017;176(1):100-106. 30. Maunder RG. Panic disorder associated with gastrointestinal 8. Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, disease: Review and hypotheses. J Psychosom Res pathogenesis, and subtype classification. J Am Acad Dermatol 1998;44(1):91-105. 2004;51(3):327-341; quiz 342-344. 31. Singh P, Agnihotri A, Pathak MK, et al. Psychiatric, somatic and 9. Wollina U. Recent advances in the understanding and other functional gastrointestinal disorders in patients with management of rosacea. F1000Prime Rep 2014;6:50. irritable bowel syndrome at a tertiary care center. J 10. Drummond PD, Su D. Endothelial and axon reflex Neurogastroenterol Motil 2012;18(3):324-331. vasodilatation to acetylcholine in rosacea-affected skin. Arch 32. de Montigny C. Cholecystokinin tetrapeptide induces panic-like Dermatol Res 2012;304(2):133-137. attacks in healthy volunteers. Preliminary findings. Arch Gen 11. Dayan SH, Pritzker RN, Arkins JP. A new treatment regimen for Psychiatry 1989;46(6):511-517. rosacea: onabotulinumtoxinA. J Drugs Dermatol 33. Fertleman CR, Baker MD, Parker KA, et al. SCN9A mutations 2012;11(12):e76-e79. in paroxysmal extreme pain disorder: allelic variants underlie 12. Schwab VD, Sulk M, Seeliger S, et al. Neurovascular and distinct channel defects and phenotypes. Neuron neuroimmune aspects in the pathophysiology of rosacea. J 2006;52(5):767-774. Investig Dermatol Symp Proc 2011;15(1):53-62. 34. Fertleman CR, Ferrie CD, Aicardi J, et al. Paroxysmal extreme 13. Two AM, Wu W, Gallo RL, et al. Rosacea: part 1. Introduction, pain disorder (previously familial rectal pain syndrome). categorization, histology, pathogenesis, and risk factors. J Am Neurology 2007;69(6):586-595. Acad Dermatol 2015;72(5):749-758, quiz 759-760. 35. Suter MR. What are the treatment options for paroxysmal 14. Jørgensen A-HR, Egeberg A, Gideonsson R, Weinstock LB, extreme pain disorder? Pain Manage 2015;5(4):229-232. Thyssen EP, Thyssen JP. Rosacea is associated with 36. Vetter I, Deuis JR, Mueller A, et al. Na V 1.7 as a pain target – Helicobacter pylori: a systematic review and meta-analysis. J From gene to pharmacology. Pharmacol Ther 2017;172:73- Eur Acad Dermatol Venereol 2017;31(12):2010-2015. 100. 15. Spoendlin J, Karatas G, Furlano RI, et al. Rosacea in patients 37. Dib-Hajj SD, Estacion M, Jarecki BW, et al. Paroxysmal with ulcerative colitis and Crohns Disease: A population- extreme pain disorder M1627K mutation in human Nav1.7 based case-control study. Inflamm Bowel Dis 2016;22(3):680- renders DRG neurons hyperexcitable. Mol Pain 2008;4:37. 687. 38. Darbar A, Bilolikar A. Case reports: anesthesia for a patient with 16. Abokwidir M, Feldman SR. Rosacea Management. Skin paroxysmal extreme pain disorder. Anesth Analg Appendage Disord 2016;2(1-2):26-34. 2010;110(6):1719-1720.

CM&R 2018 : 1-2 (June) Rastogi et al. 35 39. Cannon A, Kurklinsky S, Guthrie KJ, et al. Advanced Genetic ¶University of Louisville, Department of Medicine, Testing Comes to the Pain Clinic to Make a Diagnosis of Gastroenterology, Hepatology and Nutrition. Director, Paroxysmal Extreme Pain Disorder. Case Rep Neurol Med Fellowship Training Program, Director, Medical Procedure 2016;2016:9212369. Unit Louisville VAMC 401 East Chestnut Street, Louisville, 40. Deng M, Nedorost S. Facial flushing: an uncommon presentation of serotonin toxicity. Dermatitis 2009;20(5):296- KY 40202. 297. 41. Hair PI, Curran MP, Keam SJ. Tramadol extended-release tablets. Drugs 2006;66(15):2017-2027; discussion 2028-2030. 42. Curran CF. Doxorubicin-associated facial flushing. Arch Dermatol 1992;128(10):1408. 43. Quertemont E. Genetic polymorphism in ethanol metabolism: acetaldehyde contribution to alcohol abuse and alcoholism. Mol Psychiatry 2004;9(6):570-581. 44. Sticherling M, Brasch J. Alcohol: intolerance syndromes, urticarial and anaphylactoid reactions. Clin Dermatol 1999;17(4):417-422. 45. Becker K, Southwick K, Reardon J, Berg R, MacCormack JN. Histamine poisoning associated with eating tuna burgers. JAMA 2001;285(10):1327-1330. 46. Ferran M, Yébenes M. Flushing associated with scombroid fish poisoning. Dermatol Online J 2006;12(6):15. 47. Freeman M. Reconsidering the effects of monosodium glutamate: A literature review. J Am Acad Nurse Pract 2006;18(10):482-486. 48. Lurie Y, Wasser SP, Taha M, et al. Mushroom poisoning from species of genus Inocybe (fiber head mushroom): a case series with exact species identification. Clin Toxicol 2009;47(6):562- 565. 49. Vally H, Misso NLA, Madan V. Clinical effects of sulphite additives. Clin Exp Allergy 2009;39(11):1643-1651. 50. Mosqueda-Garcia R. Adenosine as a therapeutic agent. Clin Invest Med 1992;15(5):445-455. 51. Sidi V, Arsos G, Papakonstantinou E, et al. Use of amifostine in the treatment of recurrent solid tumours in children. Hippokratia. 2007;11(1):25-29. 52. Aronson JK, ed. Meyler’s side effects of drugs: The international encyclopedia of adverse drug reactions and interactions. 16th ed. Waltham, MA: Elsevier BV; 2016. 53. Vieth M, Montgomery E. Medication-associated gastrointestinal tract injury. Virchows Arch 2017;470(3):245-266. 54. Kulisevsky J, Pagonabarraga J. Tolerability and safety of ropinirole versus other dopamine agonists and levodopa in the treatment of Parkinson’s disease: meta-analysis of randomized controlled trials. Drug Saf 2010;33(2):147-161. 55. Goldstein I, Tseng LJ, Creanga D, Stecher V, Kaminetsky JC. Efficacy and Safety of Sildenafil by Age in Men With Erectile Dysfunction. J Sex Med 2016;13(5):852-859.

Author Affiliations Vaibhav Rastogi, MD*,†; Devina Singh, MD‡; Joseph J Mazza, MD§; Dipendra Parajuli, MD¶, Steven H Yale, MD*,†

*University of Central Florida College of Medicine/HCA Consortium Graduate Medical Education, North Florida Regional Medical Center, 6500 W Newberry Rd, Gainesville, FL 32605. †University of Central Florida College of Medicine, 6850 Lake Nona Blvd, Orlando, FL 32827. ‡Feinstein Institute for Medical Research, 350 Community Dr. Manhasset, NY 11030 §Marshfield Clinic Research Institute, 1000 North Oak Avenue, Marshfield, WI 54449.

36 Flushing associated with gastrointestinal system CM&R 2018 : 1-2 (June)